JP2012201597A - Solid preparation comprising mosapride - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prevent formation of a decomposate of mosapride or a physiologically acceptable salt thereof.SOLUTION: The solid preparation comprises mosapride or a physiologically acceptable salt thereof and contains a saccharide nonhydrate and/or a sugar alcohol nonhydrate.

Description

  The present invention relates to 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide (hereinafter also referred to as “mosapride”) or physiologically thereof. The present invention relates to a solid preparation containing an acceptable salt, and in particular, to a solid preparation containing mosapride or a physiologically acceptable salt thereof and a saccharide anhydride and / or a sugar alcohol anhydride.

  Mosapride is a compound used for the treatment of gastrointestinal symptoms associated with chronic gastritis, such as heartburn, nausea and vomiting. Mosapride citrate dihydrate, which is a physiologically acceptable salt of the compound, has already been put into practical use. The commercialized product is marketed in Japan under the trade name of Gasmotin (trademark). The product is a tablet containing 2.5 mg or 5 mg of mosapride citrate. The tablet contains lactose hydrate, corn starch, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium stearate, light anhydrous silicic acid, hypromellose, macrogol 6000, titanium oxide and talc as additives. Also, since mosapride citrate exhibits a bitter taste, the tablet is in the form of a film-coated tablet. Also, mosapride decomposes under long-term storage to produce a decomposition product. In order to prevent the decomposition products from being produced, the tablets are provided with aluminum packaging. The decomposition product is generally called a related substance. The 15th revision Japanese Pharmacopoeia Second Supplement describes the purity test of mosapride citrate tablets and stipulates that the amount of related substances must be within a certain range in the purity test.

  In the following Patent Document 1, “4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide (hereinafter referred to as“ Compound A ”) or its A fast-dissolving film-coated tablet containing a physiologically acceptable salt ”is described (Claim 1), and the film-coated tablet contains“ (a) Compound A or a physiologically acceptable salt thereof ” The surface of the uncoated tablet and (b) the uncoated tablet is substantially free of a plasticizer, or (omitted) has a coating layer including at least one specific formulation component ”(Claim 1). ing. The compound A is “(±) -4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide (hereinafter referred to as“ mosapride ”). Is mosapride, as described in the first page (lines 8-10).

International Publication No. 2006/011637

  Mosapride decomposes over time to produce degradation products. Accordingly, it is necessary to improve the storage stability of a solid preparation containing mosapride or a physiologically acceptable salt thereof by suppressing the production of the decomposition product. Then, an object of this invention is to prevent the production | generation of the decomposition product of a mosapride. That is, an object of the present invention is to improve the storage stability of a solid preparation containing mosapride or a physiologically acceptable salt thereof.

  The present invention provides a solid formulation comprising mosapride or a physiologically acceptable salt thereof. The solid preparation contains a saccharide anhydride and / or a sugar alcohol anhydride.

  In the present invention, the combination of mosapride or a physiologically acceptable salt thereof and a saccharide anhydride and / or a sugar alcohol anhydride can suppress the decomposition of mosapride, resulting in the generation of a decomposition product. Can be prevented. Therefore, the solid preparation according to the present invention is excellent in storage stability. Furthermore, in the solid preparation according to the present invention, the decomposition of mosapride is suppressed without applying a special film coating as described in Patent Document 1 above. Furthermore, the present invention can eliminate the need for protective packaging such as aluminum packaging that has been conventionally used to prevent the decomposition of mosapride.

  Mosapride is also referred to as 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide. Mosapride may be a racemate or one of the optically active forms, but a racemate is preferred. Mosapride has a good gastrointestinal motility promoting action as a selective serotonin 4 receptor agonist. Mosaprid can be produced, for example, by the method described in US Pat.

により表される化合物である。本発明において、固形製剤に含まれるモサプリド又はその塩の重量割合は、固形製剤の全重量に対して、０．５〜１０重量％、特には１〜８重量％、より特には１．５〜６重量％、さらにより特には２〜５重量％である。この割合によって又はこの割合と下記糖類無水和物及び／又は糖アルコール無水和物の割合との組合せによって、モサプリド又はその塩の分解が抑制されうる。 In the present invention, the physiologically acceptable salt of mosapride is preferably an acid addition salt. Among acid addition salts, examples of organic acid addition salts include formate, acetate, lactate, adipate, citrate, tartrate, fumarate, methanesulfonate, maleate and the like. Examples of inorganic acid addition salts include hydrochlorides, sulfates, nitrates, phosphates, and the like. Of these acid addition salts, citrate is particularly preferred. Furthermore, mosapride or a physiologically acceptable salt thereof may be a solvate, a hydrate or a non-hydrate. Citrate hydrate is preferred, and citrate dihydrate is particularly preferred. Mosaprid citrate dihydrate has the following formula:

It is a compound represented by these. In the present invention, the weight ratio of mosapride or a salt thereof contained in the solid preparation is 0.5 to 10% by weight, particularly 1 to 8% by weight, more particularly 1.5 to 5%, based on the total weight of the solid preparation. 6% by weight, even more particularly 2-5% by weight. The decomposition of mosapride or a salt thereof can be suppressed by this ratio or by a combination of this ratio and the ratio of the following sugar anhydride and / or sugar alcohol anhydride.

  In the present invention, a saccharide anhydride refers to a saccharide that does not contain hydrated water. That is, a saccharide anhydrate is a saccharide whose water molecule is 0 in terms of chemical structure. The sugar alcohol anhydride refers to a sugar alcohol that does not contain hydrated water. That is, a sugar alcohol anhydride is a sugar alcohol having a water molecule of 0 in terms of chemical structure. Hydrated water is also called crystal water. In the present invention, it is considered that the decomposition of mosapride or a salt thereof is suppressed by the presence of saccharide anhydride and / or sugar alcohol anhydride.

  In the present invention, the saccharide anhydride is in particular a disaccharide or monosaccharide anhydride, such as sucrose anhydride, lactose anhydride, grape sugar anhydride, fructose anhydride, maltose anhydride. , Trehalose anhydride, galactose anhydride and / or mannose anhydride, preferably saccharose anhydride and / or trehalose anhydride from the viewpoint of inhibiting decomposition of mosapride or a salt thereof, particularly preferably trehalose It is non-hydrated. These sugar anhydrides are commercially available. Examples of the sucrose anhydrous include frost sugar FS2 (Nisshin Sugar Co., Ltd.), and examples of the trehalose anhydride include Trehalose P (Asahi Kasei Chemicals Corporation). In the present invention, the weight ratio of the saccharide anhydride contained in the solid preparation is 5 to 90% by weight, preferably 10 to 80% by weight, more preferably 30 to 78% by weight, based on the total weight of the solid preparation. More preferably, it is 50 to 75% by weight, and still more preferably 60 to 70% by weight. The decomposition of mosapride or a salt thereof can be suppressed by this ratio or by a combination of this ratio and the weight ratio of the mosapride or a salt thereof.

  In the present invention, the sugar alcohol anhydride is, for example, D-mannitol anhydride, sorbitol anhydride, xylitol anhydride, erythritol anhydride, maltitol anhydride, isomalt anhydride, lactitol anhydride. , Arabitol anhydrate, galactitol anhydrate and / or ribitol anhydrate, preferably D-mannitol anhydrate, sorbitol anhydrate, xylitol anhydrate from the viewpoint of inhibiting decomposition of mosapride or a salt thereof. Product, erythritol anhydride and maltitol anhydride, one or more sugar alcohol anhydrides, particularly preferably D-mannitol anhydride. These sugar alcohol anhydrides are commercially available. D-mannitol anhydride is, for example, Mannit P (Mitsubishi Corporation Food Tech Co., Ltd.). The erythritol anhydrous is, for example, erythritol (Product Food Science Co., Ltd.). The sorbitol anhydrous is, for example, sorbitol (Product Food Science Co., Ltd.). Xylitol anhydrate is, for example, xylitol (product food science corporation). Maltitol anhydrate is, for example, Amarti MR (Mitsubishi Corporation Food Tech Co., Ltd.). In the present invention, the weight percentage of sugar alcohol anhydride contained in the solid preparation is 5 to 90% by weight, preferably 10 to 80% by weight, more preferably 30 to 78% by weight, based on the total weight of the solid preparation. Even more preferably, it is 60 to 70% by weight. The decomposition of mosapride or a salt thereof can be suppressed by this ratio or by a combination of this ratio and the weight ratio of the mosapride or a salt thereof.

  In the present invention, the ratio of the total weight of saccharide anhydride and sugar alcohol anhydride contained in the solid preparation is 5 to 90% by weight, preferably 10 to 80% by weight, based on the total weight of the solid preparation. Preferably it is 30-78 weight%, More preferably, it is 60-70 weight%. The decomposition of mosapride or a salt thereof can be suppressed by this ratio or by a combination of this ratio and the weight ratio of the mosapride or a salt thereof.

The solid preparation of the present invention can take forms such as, but not limited to, tablets, pills, powders, fine granules, granules, capsules and the like. The solid preparation of the present invention is preferably a tablet from the viewpoint of inhibiting the decomposition of mosapride or a salt thereof. The tablet may be film-coated. That is, the tablet can be a film-coated tablet. The film coating may be those commonly used in the art. The tablet can be an orally disintegrating tablet. An orally disintegrating tablet is a tablet that disintegrates easily in the oral cavity, and in particular, the tablet is saliva in the oral cavity while maintaining the ease of handling of the tablet by having an appropriate strength that does not collapse in the distribution process. Or it is a preparation that is easy to swallow by disintegrating with a small amount of water. The orally disintegrating tablet can be manufactured by techniques known in the art.

  The solid preparation of the present invention may contain formulation ingredients such as an excipient, a disintegrant, a binder, a fluidizing agent, and a split lubricant. In the present invention, the saccharide anhydride and / or sugar alcohol anhydride can also serve as an excipient.

  In the present invention, examples of the disintegrant include low-substituted hydroxypropylcellulose, crospovidone, carmellose, carmellose calcium, sodium carboxypropyl starch, and partially pregelatinized starch. Among these disintegrants, low-substituted hydroxypropylcellulose is preferable as a disintegrant from the viewpoint that a disintegration delay due to heat or humidity hardly occurs. The content of the disintegrant may be common in the art, and may be usually 1 to 20% by weight, preferably 5 to 15% by weight, based on the total weight of the agent. In the present invention, 1 to 20% by weight means 1% by weight or more and 20% by weight or less.

  In the present invention, examples of the binder include hydroxypropylcellulose, starch paste, povidone, polyvinyl alcohol, dextrin, and carmellose sodium. In the present invention, hydroxypropylcellulose, starch paste, povidone and polyvinyl alcohol are preferred as binders from the viewpoint of easy formulation. The blending amount of the binder may be common in the art, and is usually 1 to 10% by weight, preferably 1 to 5% by weight, based on the total weight of the agent.

  In the present invention, formulation ingredients such as fluidizing agents such as light anhydrous silicic acid and hydrous silicon dioxide, splitting agents such as magnesium stearate, sucrose fatty acid ester and hydrogenated oil are blended with the agent of the present invention as necessary. May be.

  The solid formulation of the present invention may have a film coating. In the film coating, a film base, a plasticizer, a colorant, an anti-sticking agent, a brightening agent and the like may be appropriately blended as necessary. The film coating may be those commonly used in the art.

  The solid preparation of the present invention can be produced according to a known method (for example, a method described in the 15th revised Japanese Pharmacopoeia General Rules for Preparations). For example, in the case of tablets, mosapride or a physiologically acceptable salt thereof, saccharide anhydride or sugar alcohol anhydride, and other formulation ingredients such as excipients are mixed, and a binder is added to form granules. The granules can be tableted into tablets. Pills, powders, fine granules, granules, and capsules can also be produced according to methods known in the art.

The present invention will be described below with reference to examples, but the present invention is not limited to these examples.
In the following examples, the production rate of related substances was measured. A related substance is a decomposition product of mosapride. The production rate of the related substance is an indicator of the storage stability of the agent. The smaller the production rate of the related substance, the better. The smaller the proportion of related substances produced in the agent, the better the storage stability of the agent. The above measurement was performed as follows. That is, 20 or more of the manufactured agents were taken to obtain powder. An amount of the powder corresponding to 10 mg of mosapride citrate (C ₂₁ H ₂₅ ClFN ₃ O ₃ .C ₆ H ₈ O ₇ ) was taken, and 1 mL of water was added to the amount of powder to moisten. Furthermore, 9 mL of methanol was added and shaken for 20 minutes, followed by centrifugation at 3000 rpm for 10 minutes, and the supernatant was used as a sample solution. The sample solution was subjected to liquid chromatography under the following test conditions.

Test condition detector: UV spectrophotometer (measurement wavelength: 274 nm)
Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm filled with 5 μm of octadecylsilylated silica gel for liquid chromatography (GL Science Inc., Inertsil ODS-2)
Column temperature: Constant temperature mobile phase around 40 ° C. A: Dissolved 8.82 g of trisodium citrate dihydrate in 800 mL of water, adjusted to pH 4.0 with dilute hydrochloric acid, and then added water to 1000 mL Mobile phase B: Acetonitrile mobile phase feed: Concentration gradient control was performed by changing the mixing ratio of mobile phase A and mobile phase B as follows

  Based on the results of liquid chromatography under the above test conditions, a total peak area and a total peak area of related substances were obtained by an automatic integration method. The peak area of the related substance is the peak area other than the mosapride peak from the solvent peak to 40 minutes after the injection. The total peak area is the total area of peaks other than the mosapride peak from the solvent peak to 40 minutes after injection. (Total peak area of related substances / total peak area) × 100 is the production ratio (% by weight) of related substances.

  Mosaprid citrate dihydrate ("Mosaprid citrate hydrate" 7.58g in the 15th revision Japanese Pharmacopoeia Second Supplement, D-mannitol Anhydrate (Mannit P: Mitsubishi Corporation Foodtech Co., Ltd.) 147 g and corn starch (corn starch: Nippon Food Processing Co., Ltd.) 17 g were weighed and mixed with a stirring granulator (FM-VG-01: Paulek Co., Ltd.) After mixing, hydroxypropylcellulose (HPC-SSL) : Nippon Soda Co., Ltd.) A binder solution prepared by dissolving 6 g in 24 g of water was added to the mixture and kneaded, and after kneading, the kneaded material was passed through a sieve having an opening of 1140 μm, and a fluidized bed granulator (FD -MP-01: Paurec Co., Ltd. After drying, the mixture was sized with a sieve having an opening of 710 μm to obtain granules.

  Low-substituted hydroxypropyl cellulose (LH-22: Shin-Etsu Chemical Co., Ltd.) 40 g, light anhydrous silicic acid (Adsolider 101: Freund Sangyo Co., Ltd.) 0.4 g, magnesium stearate (magnesium stearate (vegetable)) : Taihei Chemical Industry Co., Ltd.) 1.6 g was added to obtain a powder for tablets.

  Using a rotary tableting machine (ultra-small rotary tableting machine VELA5: Kikusui Seisakusho Co., Ltd.), the tablet powder is 150 mg oval tablet (long diameter: 9.08 mm, short diameter: 4.54 mm) per tablet. Tableting was performed so that the hardness was 60 N to 90 N, and an uncoated tablet (hereinafter referred to as “Uncoated tablet of Example 1”) was obtained. Table 1 below shows the composition of the uncoated tablets.

  An uncoated tablet (hereinafter referred to as “Uncoated tablet of Example 2”) in the same manner as in Example 1 except that erythritol anhydrous (erythritol fine powder: Mitsubishi Chemical Foods) was used instead of D-mannitol anhydrous. ) Table 1 below shows the composition of the uncoated tablets.

  An uncoated tablet (hereinafter referred to as “Example 3” in the same manner as in Example 1 except that maltitol anhydrate (powder reduced maltose syrup (Amalty MR): Mitsubishi Corporation Foodtech Co., Ltd.) was used instead of D-mannitol. No uncoated tablets). Table 1 below shows the composition of the uncoated tablets.

  An uncoated tablet (hereinafter referred to as “uncoated tablet of Example 4”) was obtained in the same manner as in Example 1 except that trehalose anhydrate (Trehalose P: Asahi Kasei Chemicals Corporation) was used instead of D-mannitol. . Table 1 below shows the composition of the uncoated tablets.

(Comparative Example 1)
An uncoated tablet (hereinafter referred to as “Uncoated tablet of Comparative Example 1”) in the same manner as in Example 1 except that lactose hydrate (lactose 200: DMV-Fonterra Experts, Germany) was used instead of D-mannitol Got. Table 1 below shows the composition of the uncoated tablets.

  10800 g of purified water from 816.0 g of hypromellose (Shin-Etsu Chemical Co., Ltd.), 81.6 g of Macrogol 6000 (Sanyo Chemical Industries Co., Ltd.), 244.8 g of titanium oxide (Freund Sangyo Co., Ltd.) and 57.6 g of talc (Matsumura Sangyo Co., Ltd.) The film coating solution was prepared by dissolving and dispersing in the solution. The uncoated tablet of Example 1 was put into a Doria Coater (Paulec Co., Ltd.), the film coating solution was sprayed, and the coating amount after drying was 5 mg per tablet. ("Film-coated tablet of Example 5") was obtained. The composition of the film coating layer is shown in Table 2 below.

(Comparative Example 2)
A film coating tablet (hereinafter referred to as “film-coated tablet of Comparative Example 2”) was obtained in the same manner as in Example 5 except that the uncoated tablet of Comparative Example 1 was used instead of the uncoated tablet of Example 1. .

(Test Example 1)
Measurement of production rate of related substances

  The tablets obtained in Examples 1, 2, 3, 4, 5 and Comparative Examples 1 and 2 were stored in a glass bottle cap at 60 ° C. for 3 days. The production rate of related substances before and after storage was measured. The measurement results are shown in Table 3 below.

  As shown in Table 3, the tablet of Comparative Example 1 had a related substance production rate of 0.40% after storage, whereas the tablets of Examples 1 to 4 had a similar substance production rate after storage. It was 0.14-0.22%. The production rate of the related substance for the tablets of Examples 1 to 4 is about half of the production rate of the related substance for the tablet of Comparative Example 1. Therefore, in the tablets of Examples 1 to 4, the decomposition of mosapride is suppressed as compared with the tablet of Comparative Example 1. That is, the tablets of Examples 1 to 4 showed better storage stability than the tablet of Comparative Example 1. The film-coated tablet of Comparative Example 2 had a related substance production rate of 0.47% after storage, whereas the film-coated tablet of Example 5 had a related substance production rate of 0.18 after storage. %Met. Therefore, in the film-coated tablet of Example 5, the decomposition of mosapride is suppressed as compared with the film-coated tablet of Comparative Example 2. That is, the film-coated tablet of Example 5 showed better storage stability than the film-coated tablet of Comparative Example 2. Moreover, the production | generation ratio of the related substance was substantially the same between the uncoated tablet of Examples 1-4 and the film coating tablet of Example 5. FIG. The production rate of the related substances was almost the same between the uncoated tablet of Comparative Example 1 and the film-coated tablet of Comparative Example 2. Therefore, the presence or absence of film coating had no effect on the production rate of related substances.

(Test Example 2)
Measurement of production rate of related substances under thermal humidity

  After the film-coated tablet of Example 5 and the film-coated tablet of Comparative Example 2 were stored at 60 ° C. or 60 ° C. and 75% RH for 5 days with a glass bottle opener, the production rate of related substances was measured. The measurement was performed by the method described in Example 6. The measurement results are shown in Table 4 below.

As shown in Table 4, the film-coated tablet of Comparative Example 2 produced 0.63% of the related substance at 60 ° C., whereas the film-coated tablet of Example 5 was 0.41%. Therefore, in the film-coated tablet of Example 5, the decomposition of mosapride was suppressed as compared with the film-coated tablet of Comparative Example 2. In addition, the film-coated tablet of Comparative Example 2 produced 0.98% of a similar substance even at a temperature of 60 ° C. and a relative humidity (RH) of 75%, whereas the film of Example 5 The coated tablet had a related substance production rate of 0.45%. Therefore, in the film-coated tablet of Example 5, the decomposition of mosapride was suppressed as compared with the film-coated tablet of Comparative Example 2. From this result, it can be seen that the solid preparation of the present invention is hardly affected by humidity.

Claims (10)

  A solid formulation containing 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide or a physiologically acceptable salt thereof, The said agent containing sugar anhydride and / or sugar alcohol anhydride.   The agent according to claim 1, wherein the sugar alcohol anhydride is D-mannitol anhydride, erythritol anhydride, maltitol anhydride, sorbitol anhydride and / or xylitol anhydride.   The agent according to claim 2, wherein the sugar alcohol anhydride is D-mannitol anhydride.   The agent according to claim 2 or 3, wherein the content of the sugar alcohol anhydride is 5% by weight to 90% by weight with respect to the weight of the agent.   2. The agent according to claim 1, wherein the saccharide anhydride is sucrose anhydride and / or trehalose anhydride.   The agent according to claim 5, wherein the saccharide anhydride is trehalose anhydride. The agent according to claim 5 or 6, wherein the content of the sugar anhydride is 5% to 90% by weight based on the weight of the agent.   The agent according to any one of claims 1 to 7, wherein the agent is a tablet.   The tablet according to claim 8, wherein the tablet is a film-coated tablet. The tablet according to claim 8, wherein the tablet is an orally disintegrating tablet.